Parvovirus B19 is transmitted between humans by aerosal inhalation. The main target cells of parvovirus B19 are erythroidprogenitor cells in bone marrow. It is not known whether the virus initially replicates in the respiratory tract before disseminationto the bone marrow or if the virus is able to cross the lung mucosa and then migrate to the bone marrow. To infect target cells,parvovirus B19 requires a primary receptor Gb4Cer (globoside) as well as co-receptors Ku80 autoantigen and α5β1 integrinthat mediate attachment and internalisation by endocytosis. The Gb4Cer receptor is found on the surface of erythrocytes,platelets and granulocytes and potentialy plays a role in transference of bound virus to other tissues. The Gb4Cer receptor isalso expressed in lung, heart, liver, kidney, synovium, endothelium and gut tissue where parvovirus B19 DNA can often bedetected. This may be involved in autoimmune reactions and viral persistence.

Parvovirus B19 infection cycle

Lungs

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ParvovirusB19

Dissemination

Liver

Kidney

Gut

Heart

Joint

Endothelium

The development of erythrocytes in bone marrow is regulated by the hormone erythropoietin that stimulates the differentiationof progenitor cells into erythroid precursor cells. A number of intermediate cell stages can be identified beginning with theproerythroblast (pronormoblast). The cell nucleus is extruded at the orthochromatic erythroblast (normoblast) stage beforeformation of an enucleated polychromatic erythrocyte (reticulocyte). These cells are released into the circulation where theymature into functional erythrocytes.

Erythropoiesis

Erythrocyte

Multipotenthaematopoietic

stem cellMyeloid

progenitorProerythroblast(pronormoblast)

Basophilicerythroblast

Polychromaticerythroblast

Orthochromaticerythroblast(normoblast)

Enucleation

Polychromaticerythrocyte

(reticulocyte)

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The main target cell of parvovirus B19 is the proerythroblast (pronormoblast) that expresses the primary receptor Gb4Cer(globoside) as well as co-receptors Ku80 autoantigen and α5β integrin required for attachment and virus internalisation byendocytosis. Due to viral cytopathic effects, the normal development of the proerythroblast is altered and fails to differentiateinto mature erythroid precursor cells. Instead, infected proerythroblasts increase in size and produce new virus particles thatassemble in the nucleus. Viral proteins such as NS1 and the 11kd protein are thought to mediate induction of apoptosis tofacilitate release of virusl particles. In severe cases of parvovirus B19 infection or in the immunocompromised, patients candevelop anaemia due to reduced formation of erythrocytes. It is also possible that increased levels of apoptosis may exposeintracellular antigens that could promote the development of autoimmune disease.

Parvovirus B19 infection disrupts erythropoiesis

Giantproerythroblast(pronormoblast)

ParvovirusB19

Apoptosis

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Multipotenthaematopoietic

stem cellMyeloid

progenitorProerythroblast(pronormoblast)

Adaptive immunity is necessary for control of parvovirus B19. Although both cell-mediated and humoral responses occur, itappears that neutralising antibodies play a dominant role in clearance of virus. This is observed during natural parvovirusB19 infection and also during treatment with IVIG. For humoral immune responses to occur, activation of CD4+ helper T cellsand B cells is necessary. CD4+ helper T cells are activated in secondary lymphoid organs by antigen presenting cells, suchas dendritic cells and macrophages, that phagocytose virus or viral antigens. Viral peptide antigens are then displayed onHLA class II receptors for interaction with the T cell receptor expressed on the surface of CD4+ helper T cells.

Parvovirus antigen uptake and viral peptide processing

ParvovirusB19

Phagocytosis

Dendriticcell

Macrophage

HLAclass II

receptorParvovirus

peptideHLAclass I

receptor

Parvoviruspeptide

Secondarylymphoid

organ

T cellzone

Apoptosis

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Antiviral CD8+ cytotoxic T cell and CD4+ helper T cell responses can be detected following parvovirus B19 infection. It hasbeen observed that these T cell responses can often remain sustained after resolution of primary infection and may relateto possible persistence of parvovirus B19 in other tissues. Naive CD8+ cytotoxic T cells require help from CD4+ helper T cellsbefore proliferation and differentiation into effectors can occur. Similarly, for antibody production, CD4+ helper T cells areneeded to activate B cells and allow them to proliferate and differentiate into plasma cells.

Parvovirus antigen presentation and T cell activation

HLAclass II

receptorParvovirus

peptideDendritic

cell

NaiveCD4+helperT cell

CD4

T cellreceptorNaive

CD8+cytotoxic

T cell

HLAclass I

receptor

CD8

T cellreceptor

Secondarylymphoid

organ

T cellzone Clonal

expansionClonal

expansion

Th1 CD4+helperT cell

T cellhelp

T cellzone

EffectorCD4+helperT cells

EffectorCD8+

cytotoxicT cells

Parvoviruspeptide

Naive B cells are primed in the germinal centres of secondary lymphoid organs where they interact with follicular dendriticcells. Follicular dendritic cells display captured virus and viral antigens on the cell surface. B cells express cell surfaceimmunoglobulins (B cell receptors) which may recognise and bind to these antigens. Binding of the B cell receptor triggersendocytosis of the receptor-antigen complex. The antigen is processed and immunogenic peptides are displayed on HLAclass II receptors on the cell surface. The B cell then migrates out of the germinal centre into the T cell zone for activationby CD4+ helper T cells.

Parvovirus antigen uptake and B cell priming

CD4+HelperT cell

HLAclass II

receptor

Folliculardendritic

cell

NaiveB cell

Endocytosis

Parvoviruspeptide

B cellzone

Secondarylymphoid

organ

B cellzone

B cells primed in the germinal centre require activation signals from CD4+ helper T cells before they can proliferate anddifferentiate into plasma cells. This interaction takes place in the T cell zone of the secondary lymphoid organs where activatedTh2 CD4+ helper T cells are present. Once activated, naive B cells differentiate into plasma cells that produce antibodies ofthe IgM class.

HLAclass II

receptorParvovirus

peptide

MatureTh2 CD4+

helperT cell

CD4

T cellreceptorNaive

B cell

IgM

T cellzone

B cellzone

Clonalexpansion

Plasmacell

EffectorCD4+helperT cells

EffectorB cells

Parvovirus antigen presentation and B cell activation

Parvovirus B19 is effectively cleared by neutralising antibodies as observed in natural infection as well as during treatmentwith IVIG. Enhanced phagocytosis is mediated by Fc receptors expressed by phagocytes that engulf opsonised virus. Immunecomplexes can be generated in the presence of large quantities of virus. Immune complexes are thought to be the cause ofskin rashes seen during parvovirus B19 infection and may also be responsible for a false-negative parvovirus antibody testing.It is also postulated that antibody-mediated autoimmune reactions may occur due to a similarity between parvovirus B19epitopes and human proteins (molecular mimicry) such as arthritis which is often associated with parvovirus B19 infection.

Parvovirus B19 opsonisation and immune complex formation

IgM

ParvovirusB19

IgG

Immunecomplexes

Fcreceptor

Phagocytosis

Macrophage